Study of Favezelimab (MK-4280) as Monotherapy and in Combination With Pembrolizumab (MK-3475) With or Without Chemotherapy or Lenvatinib (MK-7902) AND Favezelimab/Pembrolizumab (MK-4280A) as Monotherapy in Adults With Advanced Solid Tumors (MK-4280-001)

Phase 1CompletedNCT02720068

Merck Sharp & Dohme LLC481 enrolled

Overview

This is a safety and pharmacokinetics study of favezelimab as monotherapy and in combination with pembrolizumab AND favezelimab/pembrolizumab as monotherapy in adults with metastatic solid tumors for which there is no available therapy which may convey clinical benefit. Part A of this study is a dose escalation design in which participants receive favezelimab as monotherapy or favezelimab in combination with pembrolizumab. Part B is a dose confirmation design to estimate the recommended Phase 2 dose (RP2D), as determined by dose-limiting toxicity, for favezelimab in combination with pembrolizumab or pembrolizumab and lenvatinib in participants with advanced solid tumors. Part B will also assess the efficacy of favezelimab as monotherapy; favezelimab in combination with pembrolizumab with and without chemotherapy; favezelimab in combination with pembrolizumab and lenvatinib; and favezelimab/pembrolizumab as monotherapy in expansion cohorts. Participants who have completed the initial course of treatment and have investigator-determined progressive disease may be eligible for a second course of an additional 17 cycles of study treatment.

All participants who completed the first course were eligible for second course treatment after Sponsor consultation if there was investigator-determined progressive disease after initial treatment had been been completed.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

481

Conditions

Neoplasms

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Part A and Part B: Has histologically or cytologically-confirmed metastatic solid tumor. * Has measurable disease by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 1.1 criteria. * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. * Demonstrates adequate organ function. * If female, is not pregnant or breastfeeding, and if of child-bearing potential, is willing to use an adequate method of contraception for the course of the study and for at least 180 days after the last dose of chemotherapy, 120 days after the last dose of pembrolizumab or favezelimab, or 30 days after the last dose of lenvatinib, whichever occurs last. * If male with a female partner(s) of child-bearing potential, both must agree to use an adequate method of contraception starting with the first dose of study drug through 95 days after the last dose of study drug. Exclusion Criteria: * Has had chemotherapy, radiation or biological cancer therapy within 4 weeks prior to the first dose of study drug, or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 0 or 1 from the AEs due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related \[ir\]AEs). * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug. * Has received previous treatment with another agent targeting the lymphocyte-activation gene 3 (LAG-3) receptor. * Has received previous treatment with an immunomodulatory therapy (e.g., anti-programmed cell death-1/anti-programmed cell death-ligand 1 \[anti-PD-1/anti-PD-L1\] or cytotoxic T-lymphocyte-associated protein 4 \[CTLA 4\] agent) and was discontinued from that therapy due to a Grade 3 or higher irAE. * Is expected to require any other form of antineoplastic therapy while on study. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in excess of replacement doses, or on any other form of immunosuppressive medication. * Has a history of a previous, additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years. Time frame exceptions include successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer, or other in situ cancers. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. * Has had a severe hypersensitivity reaction to treatment with another monoclonal antibody. * Has an active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy. * Has an active infection requiring therapy. * Has history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. * Has had a prior stem cell or bone marrow transplant. * Has a known history of or screens positive for Human Immunodeficiency Virus (HIV), active chronic or acute Hepatitis B or Hepatitis C. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. * Is a regular user as determined by investigator judgement (including "recreational use") of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol), at the time of signing informed consent. * Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible. * Has clinically significant heart disease that affects normal activities. * Has received a live-virus vaccine within 30 days of planned start of study drug. Seasonal flu vaccines that do not contain live virus are permitted.

Outcomes

Primary Outcomes

Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)

DLTs were assessed during the first cycle (21 days) \& were defined as: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except Gr 4 thrombocytopenia of any duration or Gr 3 thrombocytopenia associated with bleeding; Gr 3 nonhematologic toxicity lasting ≥3 days despite optimal supportive care (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention was required, lead to hospitalization, or persisted for \>1 week); Gr 3 or 4 febrile neutropenia; any drug-related AE that caused the participant to discontinue treatment during Cycle 1; Grade 5 toxicity; Any treatment-related toxicity that causes ≥2-week delay in initiation of Cycle 2.

Time frame: Up to 21 days (Cycle 1)

Number of Participants Who Experienced an Adverse Event (AE)

An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented.

Time frame: Up to approximately 31.3 months

Number of Participants Who Discontinued Study Treatment Due to an AE

Time frame: Up to approximately 28.3 months

Secondary Outcomes

Objective Response Rate (ORR) for Part B Participants

ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experienced a CR or PR is presented.

Time frame: Up to approximately 92 months

Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Favezelimab

Blood for serum samples was collected at pre-specified time points to determine the AUC0-inf of favezelimab. In addition to time points listed in Time Frame, participants enrolled in mainland China also had samples drawn predose on Day 1 of Cycle 5 and postdose on Day 2 of Cycles 4 and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.

Time frame: Predose, 2 hours post start of infusion, and post infusion on Day 1 of cycles 1-4 and 8; Day 2 postdose in cycle 1; Days 8 and 15 in cycles 2, 4, and 8; and at the discontinuation and safety follow-up visit if performed prior to the end of Cycle 8

Area Under the Curve From Time 0 to 21 Days (AUC0-21 Days) of Favezelimab

Blood for serum samples was collected at pre-specified time points to determine the AUC0-21 Days of favezelimab. In addition to time points listed in Time Frame, participants enrolled in mainland China also had samples drawn predose on Day 1 of Cycle 5 and postdose on Day 2 of Cycles 4 and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.

Maximum Serum Concentration (Cmax) of Favezelimab

Blood for serum samples was collected at pre-specified time points to determine the Cmax of favezelimab. In addition to time points listed in Time Frame, participants enrolled in mainland China also had samples drawn predose on Day 1 of Cycle 5 and postdose on Day 2 of Cycles 4 and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.

AUC0-inf of Pembrolizumab

Blood for serum samples was collected at pre-specified time points to determine the AUC0-inf of pembrolizumab. In addition to time points listed in Time Frame, participants enrolled in mainland China also had samples drawn predose on Day 1 of Cycle 5 and postdose on Day 2 of Cycles 4 and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.

AUC0-21 Days of Pembrolizumab

Blood for serum samples was collected at pre-specified time points to determine the AUC0-21 Days of pembrolizumab. In addition to time points listed in Time Frame, participants enrolled in mainland China also had samples drawn predose on Day 1 of Cycle 5 and postdose on Day 2 of Cycles 4 and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.

Cmax of Pembrolizumab

Blood for serum samples was collected at pre-specified time points to determine the Cmax of pembrolizumab. In addition to time points listed in Time Frame, participants enrolled in mainland China also had samples drawn predose on Day 1 of Cycle 5 and postdose on Day 2 of Cycles 4 and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.

Predose Serum Concentration of Favezelimab

Blood for serum samples was collected at pre-specified time points to determine the predose serum concentration of favezelimab, which is presented.

Time frame: Predose on Day 1 of cycles 1-4, 6, and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.

AUC0-inf of Lenvatinib

Blood for serum samples was collected at pre-specified time points to determine the AUC0-inf of lenvatinib.

Time frame: Up to 4 hours postdose, and between 6-10 hours postdose on Cycle 1 Day 1; Predose and between 2-12 hours postdose on Cycle 1 Day 15; Predose, between 0.5-4 hours postdose, and between 6-10 hours postdose on Cycle 2 Day 1

AUC0-21 Days of Lenvatinib

Blood for serum samples was collected at pre-specified time points to determine the AUC0-21 Days of lenvatinib.

Cmax of Lenvatinib

Blood for serum samples was collected at pre-specified time points to determine the Cmax of lenvatinib.